Adrenal Insufficiency: Diagnosis and Management
Diagnosis
Obtain early-morning (8 AM) serum cortisol and plasma ACTH immediately when adrenal insufficiency is suspected, but never delay emergency treatment for diagnostic confirmation if the patient is clinically unstable. 1, 2
Initial Diagnostic Approach
Morning cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH in the presence of acute illness is diagnostic of primary adrenal insufficiency and requires no further testing before initiating treatment. 1, 2
Morning cortisol <400 nmol/L (<14 μg/dL) with elevated ACTH raises strong suspicion and warrants immediate treatment if the patient is symptomatic. 1
Cortisol levels between 250–550 nmol/L (9–20 μg/dL) require cosyntropin stimulation testing to definitively confirm or exclude adrenal insufficiency. 1, 3
Cosyntropin (Synacthen) Stimulation Test Protocol
Administer 0.25 mg (250 μg) cosyntropin intramuscularly or intravenously. 1, 3
Measure serum cortisol at baseline, 30 minutes, and 60 minutes post-administration. 1, 3
Peak cortisol <500–550 nmol/L (<18–20 μg/dL) at either 30 or 60 minutes is diagnostic of adrenal insufficiency. 1, 3
Peak cortisol >550 nmol/L (>20 μg/dL) excludes adrenal insufficiency. 1, 3
Distinguishing Primary from Secondary Adrenal Insufficiency
Primary adrenal insufficiency: Low cortisol with high ACTH, often accompanied by hyponatremia (90% of cases) and hyperkalemia (50% of cases). 1, 2, 3
Secondary adrenal insufficiency: Low cortisol with low or inappropriately normal ACTH, hyponatremia may be present but hyperkalemia is absent. 3, 4
Etiologic Workup for Primary Adrenal Insufficiency
Measure 21-hydroxylase autoantibodies (21OH-Ab) first, as autoimmune adrenalitis accounts for approximately 85% of primary adrenal insufficiency cases in Western populations. 1
If autoantibodies are negative, obtain CT imaging of the adrenal glands to evaluate for hemorrhage, tuberculosis (look for calcifications), tumors, metastases, or infiltrative processes. 1
In males with negative autoantibodies, measure very long-chain fatty acids (VLCFA) to screen for adrenoleukodystrophy. 1
Critical Diagnostic Pitfalls
The absence of hyperkalemia does not exclude primary adrenal insufficiency—it is present in only 50% of cases. 2, 3
Hyponatremia is present in 90% of newly diagnosed cases and can mimic SIADH; always exclude adrenal insufficiency before diagnosing SIADH. 2, 3
Exogenous steroids (prednisone, dexamethasone, inhaled fluticasone) suppress the HPA axis and confound diagnostic testing—do not attempt diagnostic confirmation until adequate washout time has elapsed. 3
Acute Adrenal Crisis Management
Administer hydrocortisone 100 mg IV bolus immediately upon clinical suspicion of adrenal crisis, followed by 0.9% isotonic saline 1 L over the first hour—treatment must never be delayed for diagnostic confirmation. 2, 5
Immediate Emergency Management (First Hour)
Give hydrocortisone 100 mg IV bolus immediately; this dose saturates 11β-hydroxysteroid dehydrogenase type 2 to provide both glucocorticoid and mineralocorticoid effects. 2, 5
Initiate aggressive fluid resuscitation with 0.9% isotonic saline at 1 L over the first hour to address profound volume depletion. 2, 5
Draw blood for cortisol, ACTH, electrolytes (sodium, potassium), creatinine, urea, and glucose before treatment if feasible, but do not wait for results. 2, 5
If IV access cannot be rapidly established, give hydrocortisone 100 mg IM as an alternative. 2
Ongoing Management (First 24–48 Hours)
Continue hydrocortisone 200 mg per 24 hours as continuous IV infusion (preferred) or 50 mg IV/IM every 6 hours as an alternative. 2, 5
Provide a total of 3–4 L of isotonic saline or 5% dextrose-in-saline over 24–48 hours, with frequent hemodynamic monitoring to avoid fluid overload. 2, 5
Monitor serum electrolytes frequently to guide fluid management. 2, 5
Administer gastric stress-ulcer prophylaxis and low-dose heparin for DVT prophylaxis. 2
Treat precipitating infections promptly with appropriate antimicrobial therapy—infections are the most common trigger of adrenal crisis. 2, 6
Perform frequent blood glucose monitoring, especially in children who are more vulnerable to hypoglycemia. 2
Admit patients with persistent hypotension to an ICU or high-dependency unit. 2
Transition to Maintenance Therapy
Taper parenteral glucocorticoids over 1–3 days once the precipitating illness permits and oral intake is tolerated. 2
Restart fludrocortisone when the hydrocortisone dose falls below 50 mg per day, as lower doses no longer provide adequate mineralocorticoid activity. 2, 5
Common Precipitating Factors to Investigate
Gastrointestinal illness with vomiting/diarrhea (most frequent trigger). 2, 6
Medication non-compliance or failure to increase doses during illness. 2, 6
Myocardial infarction and severe allergic reactions. 2
Critical Pitfalls in Acute Crisis Management
Never postpone treatment to obtain diagnostic confirmation—mortality increases with delayed intervention. 2, 5, 6
Do not add separate mineralocorticoid (fludrocortisone) during acute crisis, as high-dose hydrocortisone provides adequate mineralocorticoid activity. 2, 5
Dexamethasone is inadequate for primary adrenal insufficiency as it lacks mineralocorticoid activity. 2
Long-Term Hormone Replacement Therapy
All patients with confirmed adrenal insufficiency require lifelong glucocorticoid replacement therapy with hydrocortisone 15–25 mg daily in divided doses, typically 10 mg at 7:00 AM, 5 mg at 12:00 PM, and 2.5–5 mg at 4:00 PM. 1, 2, 4
Glucocorticoid Replacement
Hydrocortisone (HC) is the preferred glucocorticoid because it allows recreation of the diurnal cortisol rhythm. 1, 2
Alternative regimens include cortisone acetate 25–37.5 mg daily (requires hepatic conversion to active hydrocortisone) or prednisone 3–5 mg daily. 1, 4
Both HC and cortisone acetate are taken in 2–3 divided doses, with the first dose upon awakening and the last dose approximately 4–6 hours before bedtime. 1
Avoid dexamethasone for chronic replacement therapy. 2
Mineralocorticoid Replacement (Primary Adrenal Insufficiency Only)
Patients with primary adrenal insufficiency require fludrocortisone 50–200 μg daily as a single morning dose. 1, 5, 4
Children and younger adults may require higher doses (up to 500 μg daily). 5
Monitor adequacy by assessing for salt cravings, measuring blood pressure in supine and standing positions (to detect orthostatic hypotension), checking for peripheral edema, and measuring plasma renin activity. 5
Patients should consume unrestricted sodium salt intake and salty foods to compensate for increased renal sodium loss. 1, 5
Avoid liquorice and grapefruit juice, as they interfere with fludrocortisone and hydrocortisone metabolism. 1, 5
Monitoring Glucocorticoid Replacement
Monitoring relies primarily on clinical assessment, not serum cortisol or ACTH measurements. 1
Signs of over-replacement: weight gain, insomnia, peripheral edema—reduce dose. 1
Signs of under-replacement: lethargy, fatigue, nausea, poor appetite, weight loss, increased pigmentation—increase dose. 1
Adjust timing based on when symptoms occur during the day; some patients benefit from waking earlier to take the first dose and returning to sleep to relieve morning nausea. 2
Drug Interactions Affecting Hydrocortisone Requirements
CYP3A4 inducers increase hydrocortisone clearance and may require higher doses: phenytoin, carbamazepine, phenobarbital, rifampin, other antituberculosis drugs, barbiturates. 1, 2
CYP3A4 inhibitors decrease hydrocortisone clearance and may require lower doses: grapefruit juice, liquorice. 1, 2
Annual Follow-Up and Screening
Review patients at least annually with assessment of health, well-being, weight, blood pressure, and serum electrolytes. 1
Screen periodically for new autoimmune disorders, particularly hypothyroidism, as autoimmune adrenal insufficiency frequently coexists with other autoimmune conditions (up to 50% develop another autoimmune disorder). 1, 7
Monitor bone mineral density every 3–5 years to assess for complications of glucocorticoid therapy. 1
Patient Education and Emergency Preparedness
All patients with adrenal insufficiency must wear a medical alert bracelet and carry a steroid emergency card to inform medical personnel of their chronic condition—delays in emergency treatment can be fatal. 1, 2
Stress-Dose Glucocorticoid Education
Instruct patients to double or triple their usual oral glucocorticoid dose during minor illness (fever, vomiting, diarrhea, infection). 1, 2, 6
Provide training in intramuscular administration of hydrocortisone 100 mg for use during severe illness when oral intake is not possible. 1, 2, 4
Prescribe an emergency injectable hydrocortisone 100 mg IM kit with self-injection training. 2, 4
Educate patients on warning signs of impending adrenal crisis: severe weakness, confusion, persistent vomiting, severe abdominal pain, hypotension. 2
Prevention of Recurrent Adrenal Crises
Inadequate patient education on stress-dosing is a frequent contributor to recurrent crises—do not assume the patient is adequately educated. 2
Failure to increase glucocorticoid doses during intercurrent illness, despite prior education, markedly raises the risk of crisis. 2, 6
Evaluate patients with recurrent crises for chronic under-replacement (inadequate fludrocortisone, low salt intake), poor medication adherence, and underlying psychiatric disorders. 1, 2
Perioperative and High-Stress Situations
Minor stress (e.g., dental procedures, minor outpatient surgery): Double the usual daily dose for 1–2 days. 2
Moderate stress (e.g., colonoscopy, moderate surgery): Hydrocortisone 50–75 mg daily. 2
Major stress (e.g., major surgery, critical illness): Hydrocortisone 100–150 mg daily or 100 mg IV bolus followed by continuous infusion. 2
Continue stress-dose hydrocortisone throughout any surgical intervention without reduction until the patient is stable and can tolerate oral intake. 2
Special Considerations
Obstetric patients: Give hydrocortisone 100 mg IM at the onset of labor, then continue 200 mg per 24 hours IV infusion (or 50 mg IM every 6 hours) until after delivery. 2
When treating concurrent hypothyroidism and adrenal insufficiency, start corticosteroids several days before initiating thyroid hormone replacement to prevent precipitating adrenal crisis. 2, 3
Never attempt to discontinue hydrocortisone in patients with confirmed primary or secondary adrenal insufficiency from non-iatrogenic causes—these conditions are permanent and stopping replacement therapy will precipitate life-threatening adrenal crisis. 2